HUT57577A - Process for producing aqueous micelle solutions - Google Patents

Abstract

Described is a method of producing aqueous solutions containing mixed micelles formed from lipids and salts of gallic acids and in which active substances insoluble or only slightly soluble in water may, if required, be solubilized. The method is characterized in that mixtures of (a) solutions containing, in a water-soluble organic solvent, the lipids, the free gallic acids and, optionally, the active substances which are insoluble or only slightly soluble in water and (b) solutions containing 0.05-3 equivalents, relative to the gallic acids, of bases and, optionally, isotonizing additives and/or water-soluble active substances are prepared, the organic solvent removed by ultrafiltration, freeze-drying, vacuum distillation or reverse osmosis and the mixture thus obtained diluted, if required, with aqueous phase.

Description

FIELD OF THE INVENTION The present invention relates to a process for the preparation of vlsea or myelate solutions containing lipids and salts of bile acids, optionally soluble in water with poorly soluble or insoluble active ingredients.

Methods for the preparation of such mixed micelle solutions are known in the prior art, such as those disclosed in U.S. Patent No. 27,50570 issued to the Federal Republic of Germany.

Mixed micelle solutions formerly known in the art are assayed by killing lipids, salts of bile acids As, optionally with water-insoluble or insoluble active compounds in an organic solvent (e.g., ethanol) and then evaporating the solutions to the vessel wall to form a lipid film, which is solubilized in aqueous solutions. (Biochemistry 19, 1980, 602. Aa As Evening Pages, 615. As A Evening Pages ι laturforsoh. 52 c, 1977 · 748 pages As As Evening Pages).

However, it is very expensive to process it into a technically usable size only with considerable apparatus difficulties.

In addition to the preferred method of Ssen, for example, a method is known from Example 3 of the aforementioned U.S. Patent 27,30570, wherein such mixed micelle solutions are prepared by mixing the components and mixing them together.

However, the Finnish process has the disadvantage that it takes several days to implement, but after the reproduction of said example without the active ingredient, some very cloudy solutions can be obtained which, after approx. 340 nm, containing mixed inviteellae.

This method cannot be approx. Obtain clear solutions containing mixed myelles with a mean diameter of 10 nm.

We have now found that in such a simple and quick manner, such pure, aqueous mixed cell solutions can be prepared by a process characterized by

(a) a solution delayed in a water-miscible organic solvent containing the lipid (s), free bile acid (s) and optionally water-insoluble or poorly soluble active ingredient (s);

b) a solution containing 0.05 to 5 equivalents of base and optionally isotonic additive (s) and / or soluble active ingredient (s) based on bile acid (s), and the organic solvent is subjected to ultrasonification, lyophilization, vacuum distillation or reverse osmosis. and, if desired, the resulting yolk is diluted, if desired, with an aqueous phase.

The sub-invention of the present invention may be carried out using the same bile acids as used in the prior art mud. Suitable bile acids are 5? -Collan-24-acidic acid derivatives thereof, which are represented by the formula (I)

R 4 and R 6 together with R 4 and R 4 together represent an oxo group or a hydrogen atom, or a hydrogen atom and a hydroxy group,

X is hydroxy or -NH-GHg-COgH or -IIH-CCHgJj-SO2H.

Suitable bile acids include, by way of example, nucleic acid, glycolic acid, tauroic acid, deoxycholic acid, glycodeoxycholic acid, tauroedoxycholic acid, keno-desoxylic acid-glycolate keno-deoxy cholic acid.

For the preparation of visee mixed micellar solutions, preferably 1 to 50 g, in particular 2 to 15 g of bile acid per aqueous solution, and optionally aqueous solutions containing isotonic additive (s) and soluble active ingredient (s) are used.

For the preparation of aqueous mixed micellar solutions, the process of the present invention may use the same lipoids as used in the previously known processes.

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Suitable lipols include monoglycerides and azulfates, especially phospholipids such as sphingomyelin, plasma ogen, phosphatidylcholine, phosphatidyl ethanolamine, phosphatidylserine, phosphatidylinositol, and cardiolate. Mixtures [Dr. Otto-Albert Neumüller Chemie-Lexikon Chemie-Verlagshandlung, Stuttgart (Federal Republic of Germany) 2665, 5159, 3920 and 4045]

Aqueous solutions which are preferably contained in a solution containing 100 g of optionally isotonic and / or water-soluble active ingredient are preferably used for the preparation of the mixed mloella solutions.

- 40%, especially 5-20% lipid. The weight ratio of lipoid to bile acid is preferably between O.III and 2L, in particular between 0.8 and 2 »l.

Alkaline metal hydroxides, such as lithium hydroxide, potassium hydroxide and especially sodium hydroxide, are suitable as bases for the preparation of aqueous mixed cell solutions according to the process of the present invention, as well as certain organic nitrogen bases if they are physiologically harmless. nitrogen bases include, by way of example, ammonia as well as primary, secondary and tertiary amines, ethanolamine, diethanolamine, plperazine, morpholine, lysine, ornithine, as arginine, as Ν, Ν-dimethylglucamine , choline and especially

N-acetylglucamine; and tris-hydroxymethylamino-butane. These bases are used in an amount according to the invention so that the solutions contain from 0.05 to 5 equivalents of base, in particular from 0.5 to 2 equivalents of base.

Suitable water-soluble organic solvents are, for example, lower alcohols such as methanol, ethanol, propanol and isopropanol, and vinegar. These solvents are preferably used in an amount such that the resulting mixtures are in solution just in time. Said solvents were subjected to both vacuum distillation and reverse osmosis (TH Meltzer, Advances in Parenteral Science, United States, Marlée, Dekker Verlag, New York, 1st Edition, 72-74, 4 * 83-488). and 838-854 | Chea.- Ing.

Teoh. 61, 555-544 (1989).

If the solvent is removed by lyophilization, it is advisable to add to the solution 20 to 300 µg of aono- or diazaccharide, such as glucose or galactose, or a sugar alcohol such as sorbitol or menthol, prior to this operation.

In the case of solvent removal by ultrafiltration, a filter of up to 300,000 Dalton exclusion size is preferably used.

In the case of reverse osmosis - this procedure is reversed - the liquid to be removed is already technically used for titration - ♦♦ »e e e e e e e they are known to be removed through an asymmetric membrane without pores. Suitable for example are membranes made of polydimethylsiloxane or polyvinyl alcohol having a thickness of 0.1 to 2 μη applied to a foam or web-like protective layer. Suitable membrane modules are capillary modules and osmodules, or sheet modules · and spirally wound modules are also suitable and reference is made to the aforementioned publication (Ohem. Ing. Tech. 60, 1988, p. 590 et seq.) for the development of membrane selective membranes and their mechanism of action.

Not only can the reverse osmosis method be used to remove solvents from aqueous dispersions having a higher vapor pressure than mice, but the named process is also capable of removing solvents with lower vapor pressures, such as dimethylformamide, dimethylsulfoside or acetonitrile. .

After removal of the solvent, the resulting mixture \

may be diluted with a viscous phase if desired · A viscous phase containing up to 10 ml of neutralized bile acid and optionally further isotonic isosomal dosage (s) may be used.

Active substances that are hardly soluble or insoluble in viscera are preferably suitable for dressings with water solubility. , at room temperature no more than 2%. Such agents are, for example, bisplicidal pesticides, such as poorly soluble insectactoids or herbicides, and in particular poorly soluble pharmaceuticals.

As water-insoluble or insoluble pharmaceuticals, for example, the following groups of active compounds are useful in the preparation of the pharmaceutical compositions of the present invention.

Gestagenic ssterold hormones such as 15-ethyl-176-hydroxy-18,19-dinor-17a-pregn-4-ene-20-11-5-one (- Levonorgestrol), 15-ethyl-17β-hydroxy -18,19-dinor-17α-pregna-4,15-diene-20-yn-3-one (- Gestoden) or 1-ethyl-17β-hydroxy-11-methylene-18,19-dinor-17m -progn-4-ene-2O-in (- Dobot Sstrel), as well as estrogen-acting ssterold hormones such as 5-hydroxy-1,3,5 (10) -estratrien-17-one (· Estrone) or 19 -nor-17? -pregna-1,3? 5 (10) -triene-20-in-3? 17? -dlol (· Ethinylestradiol).

Androgenic ssterold hormones such as 17? -Hydroxy-4-ancL-rosten-3-one (- Testosterone) and its esters;

«

Antlandrogenic ssterold hormones such as 17 <x-aoethoxl-6-chloro-Σβ. » 2β-dihydro-3H-cyclopropaf-1,2] -pregna-1,4,6-

-triene-3,20-dione (- Cypoteron-aootate).

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Age only. ok, such as 11β, 17β, 21-trihydroxy-4-pregnene-3,20-dione (- Hydrooortison), α, 17α, 21α-trihydroxy-1,4-pregnadiene-3,2O-dlon (· PredLniaolon ), HB, 17?,? 21-trihydroxy-6? -methyl-1,4-pregnatriene-3,2? -dione (- methylprednisolone) and 6? -fluoro- ?, 21-dihydroxy-16? -ethyl- 1,4-pregnadiene-3,20-dione (- Difluocortolone).

Ergolines such as 3- (9,10-dihydro-6-ethyl-8a-ergolinyl) -1,1-diethylurea ("Ergolin"), 3- (2-bromo-9,10-dichloro) -1- 6-methyl-8a-ergolinyl) -1,1-diethylcarbamide (- Bromergoline) or 3- (6-ethyl-8a-orgolinyl) -1,1-diethylcarbamide (- Tergurid) ·

Antihypertensive agents (antihypertensives) such as 7α-aaethylthio-17α-hydroxy-3-oxo-4-pregn4n-21-carbonic acid γ-lactone (- Spironolactone) or 7α-acetylthio- 15β, 16β-ethylene-3-oxo-17α-pregna-1,4-diene-21,17-carbolactone («Meapirenone) ·

Anticoagulants (such as 5- [hexahydro-5-hydroxy-4- (3-hydroxy-4-ethyl-1-octene-6-ynyl) -2 (1H) -pentalenedinedylene)] - pentanoic acid (- Iloprost) .

Nervous system (psychopharmacic) drugs such as 4- (3-cyclopentyloxyl-4-ethoxyphenyl) -2-pyrrolidone (- Rolipra) and 7-chloro-1,3-dlhydro-1-acetyl-5- phenyl-2H-1,4-benzodiazepin-2-one (- diazepa).

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Carotenoids such as α-carotene and β-carotene.

They are fat-soluble vitamins such as vitamins A, D, E and K.

Particularly preferred are the β-carbolines described in European Patent Application Nos. 234,173 and 239,667, for example, 6-benzoyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl as β-carboline. and converts (· Becarnil) and isopropyl 5- (4-chlorophenoxy) -4-methoxymethyl-β-carboline-3-carboxylate (→ Gl-Phocip).

The aqueous mixed myeloma solutions prepared by the process of the present invention may optionally contain isotonizing additives from the Gal to increase the osmotic pressure of the solutions. Suitable additives include, for example, inorganic or organic salts or buffering agents, such as sodium chloride, phosphate buffer, citrate buffer, glycine buffer, citrate phosphate buffer, TRLa-HGl buffer, maleate buffer. etc., and also mono- or disaccharides such as glucose, lactose and sucrose, sugar alcohols such as mannitol, sorbitol, xylitol or glycerol, or certain water-soluble polymers such as dextran or polyethylene glycol.

These isotonizing agents are usually added to the solution at a concentration such that the osmotic pressure of the resulting aqueous mixed micelinates is optimal at 300 mosm for 5 to 1000 moss injection solutions.

In addition, aqueous mixed micellar solutions may contain additional water-soluble active ingredients to formulate combined formulations. Such combination formulations may be, for example, formulations containing a mixture of water or fat soluble vitamins or water soluble antibiotics in addition to corticoids.

The water-soluble micelle solutions are prepared, except for the conditions set forth in claim 1, by conventional methods, provided that the mixtures are heated to the temperature specified in claim 1 with vigorous stirring.

Since the lipols and some of the active ingredients are oxidation-sensitive substances, the process is conveniently carried out under an inert gas atmosphere, such as nitrogen or argon, and the resulting aqueous mixed micelle solutions are stabilized by the addition of antioxidants such as sodium ascorbate, tocopherol or sodium hydrogen sulfate.

An advantage of the process according to the invention is that it can be carried out on a technical scale much simpler than prior art processes.

Process operations necessary for carrying out the process, namely dissolution, mixing and vacuum distillation. · · · · ·

- 12 or reverse osmosis technically continuous export sheep pumpkin and not very expensive. Moreover, it is a further advantage of the process according to the invention that the thermal load of the components is lower than that of the previously known processes, in particular when reverse osmosis is used to remove solvents. Once prepared, the resulting aqueous mixed miella solution may be sterile filtered and / or heat sterilized at 100-140 ° C.

The following examples serve to further illustrate the process of the invention.

I

Example 1

400 ml of aqueous solution containing 2.138 g of sodium hydroxide are placed in a 2 liter round-bottomed flask. and 27 »g of glycolic acid. A clear mixture is formed which has a slightly yellowish color and has a pH of 6.5

The ethanol is then removed by reverse osmosis by concentrating the solution from 500 ml to 25 v aliquots in a reverse osmosis apparatus (Membra-Fil P-28, Buohol, Göppingen; DRG-1Ū00 membrane) · A pressure of 35 bar · Second In step 3, the cono concentrate is diluted to a starting volume with 3 x 5 mM neutralized glycolic acid. The resulting mixed micelle composition then contained less than 0.01 mg / ml ethanol.

The composition is as follows:

Phospholipon (Nattermann AG., Cologne, Germany) 90.0 mg Glyco-cholate 52.1 mg Sodium hydroxide 4.3 mg Water gives 1.0 ml pH value 6.6

To 800 ml of aqueous solution containing 2 x 8 g of potassium hydroxide are added 120 ml of an ethanolic solution containing 45 g of Phospholipone and 27 g of glycolic acid. A clear solution was formed and the pH was adjusted to 6.5 by addition of 0.1 N potassium hydroxide solution. The resulting solution is added with 18 g of sorbitol and stirred until completely dissolved.

The mixed micelle solution containing ethanol was then transferred to an ultrafiltration apparatus (Amicon GmbH, Witten, Federal Republic of Germany | Tlp number t DC 2 * membrane t HIP 30-20) and ultrafiltrated at a maximum membrane differential pressure of 1 bar. The volume of the ultrafiltrate removed was continuously supplemented by the addition of 10 mM neutralized glycolic acid solution. When the ultrafiltrate volume is 2 * 5 liters *, this continuous addition is discontinued and the mixed micelle solution is concentrated from 1 liter to 500 ml ·

The composition of the preparation is as follows: 1

Phospholipon 88 * 9 mg Glyco-cholate 58.0 mg Kélium hydroxide 6.4 mg Water ad 1 * 0 ml pH value 6.8

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5 · Example

Under the conditions described in Example 2, a mixed micelle solution was prepared except that the viscous solution contained 5u mg of KDTA sodium salt and the ethanol solution contained 560 mg of Cl-Phocip.

The composition of the mixed myelogenase dish thus obtained is as follows ι

Phospholipon 89.2 mg Glyco-cholate 52.5 mg Potassium hydroxide 6.1 mg Cl Phocip 1.01 mg Water give 1.0 ml

pH 6.7

Claims (6)

PATENT CLAIMS ι A process for the preparation of aqueous mixed mycelia comprising mixed micelles formed from lipids and bile acid salts, wherein the active compounds are solubilized, if desired, with water-insoluble or insoluble compounds, characterized in that: (a) a solution in a water-miscible organic solvent containing lipid (s), free bile acid (s) and, optionally, water-insoluble or poorly soluble active substance (s); and b) mixing a solution containing from 0.05 to 3 equivalents of base and optionally isotonizing additive (s) and / or water-soluble active ingredient (s) based on the bile acid (s), followed by ultrafiltration, lyophilization, vacuum distillation or reverse osmosis remove and dilute the resulting mixture with an aqueous phase if desired. Process for the preparation of mixed micelle solutions according to claim 1, characterized in that the solutions are used in such diluted form that the resulting mixtures are also solutions. The e eeee e · * e e according to any of claims 1 and 2. - Process 17 for the preparation of aqueous mixed miella solutions, characterized in that the 5-cholan-24-acid derivative of the formula (I) is used as bile year, where R 2 and R 1 and R 4 together are oxo or two hydrogen atoms or represents a hydrogen atom and a hydroxyl group, while Or a hydroxyl group X - represents a group of the formula H- (CH ₂ ) ₂ -SO H. A process for the preparation of aqueous mixed myoe solutions according to any one of claims 1 to 3, wherein the lipid is a phospholipid. The process for preparing aqueous mixed micelle solutions according to any one of claims 1 to 4, characterized in that the base is sodium hydroxide or potassium hydroxide. 6. A process for the preparation of aqueous mixed myeloma solutions according to any one of claims 1 to 3, characterized in that the water-insoluble or insoluble drug substance (s) is difficult to dissolve in water. 9 • e ··· « • ·· · * • you ·· e • eee eee • · "* e «· e « Use of aqueous mixed micelle solutions according to claim 6 for the preparation of injection solutions.